Mechanobiological antagonism of integrin β1/β3 gates YAP-driven reactionary dentinogenesis through fluid shear stress sensing

Dentin hypersensitivity (DH) is a prevalent mechanically related oral disorder. Its treatment remains challenging due to limited strategies for functional reactionary dentinogenesis. Fluid shear stress (FSS) within exposed dentinal tubules not only contributes to DH but also induces limited and disorganized dentinogenesis, thereby revealing a latent reparative potential. However, the mechanism by which odontoblasts decode different FSS magnitudes into organized reparative responses remains unclear. Here, we developed a biomimetic microfluidic platform that recapitulated the odontoblast mechanical microenvironment and enabled precise modulation and quantification of FSS exposure. Using this engineering platform, we demonstrated that integrins β1 and β3 function as force-dependent antagonistic mechanosensors that decode distinct FSS magnitudes, with integrin β1 promoting and integrin β3 suppressing Yes-associated protein (YAP) activation. Crucially, nuclear YAP levels, which reflect both abundance and localization, better indicated activation of dentinogenic genes such as dentin sialophosphoprotein and dentin matrix acidic phosphoprotein 1 than the nuclear-to-cytoplasmic ratio (N/C ratio) alone. Pharmacological elevation of nuclear YAP levels in vivo promoted functional reactionary dentinogenesis with effective intratubular occlusion, supporting the translational potential of mechanically informed reparative intervention strategies. Collectively, this study developed a microfluidic platform that mimicked the mechanical microenvironment of odontoblasts. Using this platform, we uncovered a mechanobiological axis from FSS to reparative therapy via integrin β1/β3-mediated YAP signaling. These findings advance the engineering understanding of odontoblast mechanotransduction and offer a rational strategy for designing mechanically targeted therapies for DH.